Devices for use in and on the human body are well known. The chemical composition of the surfaces of such devices plays a pivotal role in dictating the overall efficacy of the devices. Additionally, it is known that providing such devices with an antimicrobial surface is advantageous.
A wide variety of bactericidal and bacteriostatic coatings have been developed. For example, cationic antibiotics, such as polymyxin, vancomycin, and tetracycline have been used as coatings for contact lenses. Further, metal chelating agents, substituted and unsubstituted polyhydric phenols, aminophenols, alcohols, acid and amine derivatives, and quartemary ammonium have been used as antimicrobial agents for contact lenses. U.S. Pat. No. 5,472,703 discloses certain lipid compounds as antimicrobial agents for contact lenses.
However, the use of these known antimicrobial coatings has disadvantages. With the use of antibiotic coatings, microorganisms resistant to the antibiotics may develop. Chelating agent use fails to address the numbers of bacteria that adhere to the device. Some of the prior art coatings, for example phenol derivatives and cresols, can produce ocular toxicity or allergic reactions. Quarternary ammonium compounds are problematic because of their irritancy. Thus, a need exists for safe and effective antimicrobial coatings that overcomes at least some of these disadvantages.
U.S. Ser. No. 09/516,636 discloses that protamine, melittin, cecropin A, nisin, or combinations thereof, may be used as surface coatings to reduce adherence of bacteria to a device's surface and/or reduce growth of bacteria adhered to a device. Unfortunately those peptides have been found to be toxic in certain concentrations or have a limited spectrum of antimicrobial activity.
Subbalakshmi et al., FEBS Letters, 448, pgs. 62-66 (1999) discloses that the C-terminal 15 amino acid residues of melittin, retain their antibacterial activity but has greatly reduced haemolytic activity. Juvvadi et al. disclose placing the C-terminal of melittin at the N-terminal of synthetic peptides reduced mammalian cell cytotoxicity (Juvvadi et al., J. Am. Chem. Soc., vol. 118, pgs. 8989-8997 (1996)). However, the range of bacteria that were inhibited by the C-terminal peptide were decreased and the amount of peptide needed to inhibit those bacteria was increased (Subbalakshmi et al., FEBS Letters, 448, pgs. 62-66 (1999)).
Mixtures of cationic peptides have also been disclosed. For example, synthetic peptides containing lysine as the cationic moiety have been synthesized (Mor et al., J. Biol. Chem., vol. 269, pgs. 31635-31641 (1994)) as has a mixture of protamine and melittin (Aliwarga et al., Clim. Exp. Opthalmol., vol. 29, pgs. 157-160 (2001)).
Synthetic peptides that incorporate the active moieties from different cationic peptides in one single molecule have also been synthesized. For example, a series of peptides made from combinations of cecropin A and melittin were disclosed to retain most of their antibacterial efficacy (Boman et al., FEBS Letters, vol. 259, pgs. 103-106 (1989)). A hybrid of cecropin A and melittin was also synthesized and disclosed to reduce signs of infection and inflammation in an experimental model of microbial keratitis (Nos-Barbera et al., Cornea, vol. 259, pgs, 101-106 (1996)). However, the toxic regions of melittin were also retained and would be expected to induce toxicity in mammalian cells.